ABSTRACT

Context Data are limited regarding the risks and benefits of thrombolytic therapy
for acute ischemic stroke outside of clinical trials.

Objective To investigate predictors of in-hospital mortality in patients with
ischemic stroke treated with intravenous tissue plasminogen activator (tPA)
within a pooled analysis of large German stroke registers.

Design and Setting Prospective, observational cohort study conducted at 225 community and
academic hospitals throughout Germany cooperating within the German Stroke
Registers Study Group.

Patients A total of 1658 patients with acute ischemic stroke who were admitted
to study hospitals between 2000 and 2002 and were treated with tPA.

Main Outcome Measure In-hospital mortality.

Results One hundred sixty-six patients (10%) who received tPA died during hospitalization,
with 67.5% of these deaths occurring within 7 days. Factors predicting in-hospital
death after tPA use were older age (for each 10-year increment in age, adjusted
odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3-1.9) and altered level
of consciousness (adjusted OR, 3.4; 95% CI, 2.4-4.7). The overall rate of
symptomatic intracranial hemorrhage was 7.1% and increased with age. One or
more serious complications was observed in 27.2% of all patients and in 83.9%
of patients who died after tPA treatment. An inverse relation between the
number of patients treated with tPA in the respective hospital and the risk
of in-hospital death was observed (adjusted OR, 0.97; 95% CI, 0.96-0.99 for
each additional patient treated with tPA per year).

Conclusion In patients with ischemic stroke who are treated with tPA, disturbances
of consciousness and increasing age are associated with increased in-hospital
mortality.

Intravenous treatment with tissue plasminogen activator (tPA) is currently
the only approved treatment for patients with acute ischemic stroke and is
recommended in the guidelines of several national and international stroke
associations.1 However, in multicenter studies,
only 1.6%2 to 2.7%3 of
patients with ischemic stroke treated in community hospitals and 4.1%4 to 6.3%5 treated in
academic hospitals or specialized stroke centers received this treatment.
One major cause for the low treatment rates is that a large proportion of
patients are admitted more than 3 hours after symptom onset,6 the
time window for which application of tPA treatment is currently approved.
But even among patients admitted within 3 hours after stroke onset, treatment
rates are only moderate, ranging from 10.4%7 to
18.8%.3 In addition to a number of contraindications
clearly listed in the dru approval, uncertainties about selection criteria
for patients who will not benefit from thrombolysis might contribute to the
low rates of stroke patients treated with tPA in routine care.8 Clarification
of clinical factors associated with early death in patients treated with tPA
can help identify subgroups of patients with increased risks and thereby allow
clinicians to give special attention to patients who are at high risk of death
after tPA treatment.

The aim of our study was to identify predictors of in-hospital mortality
in patients with ischemic stroke treated with tPA outside of clinical trials.

METHODS

Data were assessed within the German Stroke Registers Study Group (Arbeitsgemeinschaft
Deutscher Schlaganfall Register [ADSR]). The ADSR is a network of regional
hospital-based stroke registers that monitors quality of stroke care in Germany.9 The registers include academic and community hospitals
as well as departments of neurology, internal medicine, and geriatric medicine.
In the present analyses, data from the stroke registers in Bavaria, Hamburg,10 Hesse,11 Rhineland-Palatinate,
and Westphalia12 were included. In total, 225
hospitals participated between 2000 and 2002 in the ADSR network, representing
about 10% of all 2240 German acute care hospitals.13

All registers applied a common set of variables for all stroke patients.9 Information gathered for each patient included sociodemographic
characteristics, comorbidities, neurological deficits, complications, diagnostic
procedures, admission procedures, and treatment strategies during the in-hospital
period. Data collection in the treating hospitals was standardized and each
hospital sent the documented forms to the coordinating center of the regional
stroke register. At the coordinating center, all data were checked for plausibility
and completeness and a regular external evaluation of quality of stroke care
was performed. Each regional stroke register sent the complete data set once
per year to the data pooling center of the ADSR at the University of Muenster.
Ischemic stroke patients admitted to any of the hospitals cooperating within
the ADSR network between January, 1 2000, and December 31, 2002, were included.

The following definitions were used: Age was categorized into younger
than 55 years, 55 to 64 years, 65 to 74 years, and 75 years or older; no further
age categorization was done because the number of patients aged 85 years or
older treated with tPA was too small. Diabetes mellitus was defined as elevated
fasting blood glucose level, patient self-report of diabetes, or use of antidiabetic
drugs. Hypertension was defined as systolic blood pressure of 160 mm Hg or
higher, diastolic blood pressure of 95 mm Hg or higher, or patient self-report
of treated hypertension. Previous stroke was a neurological deficit more than
24 hours prior to current event. Atrial fibrillation was documented by electrocardiogram.
Neurological deficits of stroke included motor deficits (weakness or paresis),
speech disturbances (aphasia, dysarthria), and disturbances of level of consciousness
(semiconscious, eg, not fully rousable; comatose, eg, either response to pain
only or no response at all).

Symptomatic intracranial hemorrhage (ICH) was defined as clinically
relevant bleeding (eg, deterioration of symptoms) and verification of ICH
by computed tomography (CT) or magnetic resonance imaging (MRI) scan. Increased
intracranial pressure was defined by evidence of symptomatic increased intracranial
pressure; eg, by edema, mass effect, or brain shift syndrome in CT or MRI
scan, with clinical findings. Recurrent stroke was a new neurological deficit
more than 24 hours after the current event. Pulmonary embolism was defined
by clinical and/or diagnostic findings. Epileptic seizure was a clinical diagnosis
of focal seizure, general seizure, or both in nonepileptic patients. Pneumonia
was defined by clinical and/or diagnostic findings.

Stroke was defined according to World Health Organization criteria.14 The diagnosis of ischemic stroke was confirmed by
CT or MRI scan. The experience of the individual hospital in tPA use was defined
as number of patients treated with tPA per hospital.7 Given
the fact that not all hospitals participated during the entire 3-year study
period, the mean number of patients treated with tPA per hospital per year
was defined as the total number of patients receiving tPA divided by number
of calendar years under observation for which the respective hospital provided
data and administered tPA. The effect of the number of thrombolytic therapies
per hospital per year on early outcome was assessed as a continuous and as
a discrete variable. As a discrete variable, the mean number of tPA administrations
per hospital per year was classified into categories of 5 per year, up to
more than 20. The lower cutoff of 5 or fewer tPA administrations per hospital
per year was used in previous studies to classify hospital experience in tPA
use.7,15 No major changes were
observed between 6 to 10 and 11 to 15 tPA administrations and between 16 to
20 and more than 20 tPA administrations. Thus, mean number of patients receiving
thrombolytic therapy per hospital was categorized into 1 to 5, 6 to 15, and
more than 15 thrombolytic therapies per hospital per year.

Statistical Analyses

The t test was used to test differences in
continuous variables and the χ2 test was used for differences
in proportions. Logistic regression analysis was performed to calculate odds
ratios (ORs) and corresponding 95% confidence intervals (CIs) for the probability
of death during hospitalization in patients receiving thrombolytic therapy.
In multivariate analyses, the influence of age, sex, comorbidities, and neurological
deficits on risk of early death was investigated. Possible interactions between
age, sex, comorbidities, and neurological deficits were controlled by adding
terms of interaction to the regression model. Statistical significance of
the resulting coefficients was tested using the likelihood ratio test. Significant
terms of interaction were revealed between disturbances of consciousness and
age groups (χ23=7.869; P = .048).
Therefore, the effect of age on in-hospital mortality after thrombolytic therapy
was also reported separately for disturbances of consciousness. Variables
in multivariate analyses were eliminated using backward-elimination procedure.
Because we recently demonstrated that risk of in-hospital death after thrombolytic
therapy is increased in hospitals with limited experience in its application,7 statistical analyses also controlled for the individual
hospitals’ experience in tPA administration. For assessing the fit of
the logistic regression model, the Hosmer-Lemeshow goodness-of-fit statistic
and c statistic were used. The Hosmer-Lemeshow goodness-of-fit
χ2 value was statistically not significant, indicating that
the model seems to fit well. The c statistic of the
model was 0.72, which represents the area under the receiver operating characteristic
curve and indicates an acceptable discrimination of the model. All tests were
2-tailed, and statistical significance was determined at an α level
of.05. Statistical analyses were performed with SAS software, version 8.2
(SAS Institute Inc, Cary, NC).

Ethics

The design of the study was approved by the ethics committee of the
Westphalian Board of Physicians and the University of Muenster. Identity of
individual patients was completely anonymous; thus, no specific informed consent
was obtained from patients. The investigators who performed the data analyses
were blinded to hospital identities. These identities were known only by the
coordinating center of the respective regional stroke register.

RESULTS

A total of 56 998 patients with ischemic stroke were registered
within the ADSR collaboration between January 1, 2000, and December 31, 2002.
Mean age of patients was 70.2 years; 50.5% were men. Two hundred twenty-five
hospitals participated in the ADSR network. Forty-four percent of these hospitals
were departments of neurology, 51% of internal medicine, and 4% of geriatric
medicine. Thirty-two percent of the participating hospitals provided stroke
unit services; 37% of the hospitals participated for 3 years, 34% for 2 years,
and 29% for 1 year. In 48% of the hospitals, ischemic stroke patients were
treated with tPA. Thrombolysis was administered more often in departments
of neurology (P<.001), in hospitals providing
stroke unit services (P<.001), and in facilities
treating a high number of ischemic stroke patients per year (P<.001). Sixty-seven percent of the hospitals offering tPA therapy
treated between 1 and 5 patients with thrombolysis per year, 33% of the hospitals
treated 6 to 15 patients, and 10% treated more than 15 patients per year.

During the study period, 1796 patients were treated with tPA for acute
ischemic stroke (range per hospital, 1-110). A total of 3.2% of all patients
and 11.6% of patients admitted within 3 hours of stroke onset were treated
with tPA. The median number of patients receiving thrombolysis per hospital
per year was 4 (range per hospital per year, 1-48). One hundred thirty-eight
patients were excluded from further analysis because of missing values. Because
not all registers provided comparable data on symptomatic ICH for the entire
study period, 409 additional patients were excluded from the assessment of
the impact of complications on risk of in-hospital death. The mean age of
patients treated with tPA was 64.9 years (SD, 12.2 years). Demographic and
clinical characteristics of patients who received thrombolytic therapy are
shown in Table 1.

Overall, 10.0% of patients treated with tPA died during hospitalization.
A total of 42.2% of in-hospital deaths occurred within the first 3 days and
67.5% within the first 7 days in the hospital. Percentages of patients treated
with tPA who did and did not die in the hospital are shown in Table 2 according to sociodemographic and clinical factors. In univariate
analyses, age, diabetes mellitus, disturbances of consciousness, and hospital
expertise in tPA treatment significantly influenced proportion of in-hospital
death (Table 2). After adjustment for
potential confounders, patients with a disturbed level of consciousness and
those in higher age groups were at increased risk of death during hospitalization
(Table 2). The influence of age on risk
of early death was similar if age was investigated as a continuous variable
(adjusted OR, 1.6; 95% CI, 1.3-1.9 for each 10-year increment in age).

Hospital expertise with use of tPA also was independently associated
with probability of early death after tPA treatment. The risk of in-hospital
death decreased by 3% for each additional patient treated with tPA per year
(Table 2). In-hospital mortality was
13.4% in hospitals that treated fewer than 6 patients, 11.5% in hospitals
treating 6 to 15 patients, and 7.1% in hospitals treating more than 15 patients
with tPA per year. Risk of in-hospital mortality was lower in hospitals administering
tPA 6 to 15 times and more than 15 times per year (adjusted OR, 0.8; 95% CI,
0.5-1.2 and adjusted OR, 0.5; 95% CI, 0.3-0.8, respectively; test for trend, P = .004) compared with those treating 1 to 5
patients.

Because of the differential impact of age on in-hospital mortality after
tPA treatment in patients with and without disturbances of consciousness,
multivariate analyses were stratified for this condition (Table 3). Risk of death during hospitalization increased with older
age in both of these groups. The highest absolute risk of death was observed
among patients aged 75 years or older with a disturbance of consciousness.
However, relative probability of in-hospital death in the oldest compared
with the youngest age group was particularly increased in patients without
disturbances of consciousness compared with patients with this condition (Table 3).

Table Graphic Jump LocationTable 3. Relationship of Age and In-Hospital
Mortality After tPA Treatment, Stratified by Level of Consciousness

The frequency of serious complications after tPA use and their association
with risk of in-hospital death is shown in Table
4. All assessed complications except seizures were associated with
increased risk of early mortality. Symptomatic ICH and increased intracranial
pressure were the strongest independent predictors of in-hospital death (Table 4). The rate of ICH after tPA use increased
with age, from 4.9% in patients younger than 55 years (n = 11) to
10.3% in patients aged 75 years or older (n = 31) (test for trend, P = .02) (data not shown).

COMMENT

We identified predictors of early mortality in 1658 ischemic stroke
patients treated with tPA in German hospitals. Patient and hospital characteristics
influenced risk of in-hospital death. The patient characteristics older age
and disturbed level of consciousness were independent predictors of early
mortality. Relative probability of in-hospital death was particularly increased
in older patients without disturbances of consciousness. Among hospitals,
the number of tPA administrations per year was independently associated with
early mortality. Risk of in-hospital death after thrombolysis decreased with
increasing experience of the treating hospital in tPA administration, indicating
an inverse relation.

Few studies have reported outcomes after thrombolytic therapy in old
and very old patients.16- 18 In
the National Institute of Neurological Disorders and Stroke (NINDS) trial,
only 42 patients older than 80 years were included; in the other clinical
trials on tPA, this age group was excluded.17 Based
on the limited evidence available from randomized controlled trials, the balance
of risks and benefits of thrombolysis in older patients is part of an ongoing
discussion.8,17 In a retrospective
survey of 189 patients treated with tPA outside of clinical trials, the 30
patients older than 80 years tended to be at higher risk of death during hospitalization
compared with younger patients.18 This tendency
was similar in magnitude to the impact of higher age on risk of in-hospital
mortality in our study (OR, 2.8; 95% CI, 0.8-9.618 vs
OR, 3.2; 95% CI, 1.8-5.7).

However, in our study the relative increase in risk of in-hospital death
with each age group was similar in magnitude in patients receiving tPA treatment
compared with those not treated with tPA, although absolute proportions of
death were constantly higher in tPA-treated patients. The overall rate of
in-hospital death in ischemic stroke patients not treated with tPA in hospitals
administering tPA was 4.6% (1939/41 777), increasing from 1.1% in patients
younger than 55 years up to 7.7% in patients aged 75 years or older. Older
age was an independent predictor of in-hospital death in patients not receiving
tPA treatment. The OR of death for the oldest age group (≥75 years) was
about 4-fold increased compared with the youngest group (<55 years) (OR,
4.6; 95% CI, 3.5-6.1), adjusted for sex, neurological deficits, and comorbidities.
The observational design of our study did not allow us to judge effectiveness
and benefits of treatment with tPA compared with nontreatment in older age
groups. This could best be done within the setting of randomized controlled
trials, which should specifically address effectiveness of tPA treatment in
older patients.

In our study, risk of in-hospital death after thrombolysis was independently
increased for patients with a disturbed level of consciousness, which was
identified as a predictor of stroke severity.19 Thus,
the results from our observational study are in accordance with a recently
published report of the Cochrane Stroke Group.17 In
this cumulative meta-analysis of randomized controlled trials of thrombolytic
agents in ischemic stroke, there was a statistically nonsignificant trend
toward the association of thrombolysis (all thrombolytic agents combined)
with more deaths in patients with severe strokes.17 The
highest absolute proportion of in-hospital deaths was found among patients
older than 75 years with disturbances of consciousness. However, a significant
interaction between older age and level of consciousness was observed. Relative
probability of in-hospital death increased to a larger extent with age among
patients without a disturbed level of consciousness compared with patients
with this condition. An increased risk of death in older patients might be
caused by accumulation of adverse factors with age, which independently influences
outcome. One of the most important predictors for outcome is stroke severity,20 which was defined by disturbances of consciousness
in our analysis.19 Factors influencing an increased
risk of death in older patients might also be causative for severity of stroke
in patients treated with tPA. Thus, in severe stroke patients treated with
tPA, older age might not substantially increase further risk of early death.

Overall in-hospital mortality in our study was similar to the results
of the NINDS trial (10% vs 11%21). However,
our study demonstrated substantial variations in early death depending on
the individual hospital expertise in tPA use. One possible explanation might
be the fact that the number of protocol violations is lower in hospitals with
high expertise in tPA use. A recently published overview based on approximately
2600 patients treated with tPA outside the setting of clinical trials provides
evidence that a higher proportion of protocol violations might be associated
with increased rates of death.22 This finding
is also in accordance with studies on short-term treatment of patients with
myocardial infarction, which demonstrated an independent association between
a higher volume of patients treated per hospital and better short-term survival.23,24 Our results in stroke patients receiving
thrombolytic therapy raise a question: Should tPA in routine care preferably
be administered in centers experienced in its application? To avoid potential
harm to their patients, hospitals with low numbers of tPA treatment per year
could collaborate with experienced centers in tPA use; eg, using new approaches
in networking, such as telemedicine.25

In our multicenter study, overall, 7.1% of patients treated with tPA
experienced symptomatic ICH. This rate was comparable with the NINDS trial,
which reported 6.4% with symptomatic ICH during the first 36 hours.16 However, the average rate of symptomatic ICH in a
meta-analysis of 15 open-label studies on tPA use was slightly lower (5.2%;
95% CI, 4.3-6.0)22 compared with our findings.
This difference in rates of ICH might be caused by different definitions between
the studies, especially with an ICH classification of “symptomatic.”
In addition, the rate of ICH in our study increased constantly with older
age. This finding is in accordance with a pooled analysis of data on 1205
patients collected from centers experienced in tPA use that revealed advancing
age among other causes as a factor that independently predicted the rate of
symptomatic ICH.26

Our study has several strengths and limitations. Information in our
study was collected in a uniform, prospective way in 225 community hospitals
across Germany. Observing risks of thrombolytic therapy in community settings
may provide more realistic information about the effectiveness of this procedure
in real clinical practice compared with clinical trials.27 Because
of the large number of patients, subgroup analyses among patients treated
with tPA could be performed with sufficient power. We were unable to assess
potential violations of existing thrombolysis protocols since time interval
from stroke onset to hospitalization was the only available protocol information,
and other important data such as tPA dosage, time to tPA administration, and
the National Institutes of Health Stroke Scale on admission were not documented.
In addition, no information was available about long-term outcome of patients
after discharge from the hospital since we investigated predictors for early
mortality during hospitalization. Predictors for long-term mortality after
tPA use in stroke patients might differ from factors influencing risk of in-hospital
death. Furthermore, our observational study did not aim to show a benefit
of tPA treatment vs nontreatment, which can only be done within the settings
of randomized controlled trials. We used the number of tPA applications per
year as an indicator for the expertise of an individual hospital in tPA use.
However, we cannot exclude that the inverse association between number of
tPA administrations and risk of in-hospital death might be caused by other
factors within the hospitals that improve outcome; eg, experience of treating
physician or number of physicians per hospital. Our definition of ICH was
based on clinical findings and verification of ICH on brain imaging. Thus,
we might have missed ICH if no brain imaging was performed after clinical
deterioration in a patient.

CONCLUSIONS

In this study, 10% of patients who received tPA for acute ischemic stroke
died during hospitalization, and the risk of death increased with age and
with disturbances of consciousness and was inversely associated with increasing
experience of the treating hospital in tPA administration. Thus, clinicians
should give special attention to patients with disturbances of consciousness
and older age for reducing rates of in-hospital mortality after tPA treatment.

Funding/Support: The data analyses and the
data pooling of the German Stroke Registers Study Group are funded by the
German Federal Ministry of Research (BMBF) within the Competence Net Stroke.

Role of the Sponsor: The BMBF had no role in
the design or conduct of the study; in the collection, analysis, or interpretation
or preparation of the data; or in the preparation, review, or approval of
the manuscript.

Previous Presentation: Presented in part at
the Fifth World Stroke Conference, June 24, 2004, Vancouver, British Columbia.

REFERENCES

Adams HP Jr, Adams RJ, Brott T.
et al. Guidelines for the early management of patients with ischemic stroke:
a scientific statement from the Stroke Council of the American Stroke Association. Stroke. 2003;34:1056-1083PubMed | Link to Article

Schmidt WP, Taeger D, Buecker-Nott HJ, Berger K. The impact of the day of the week and month of admission on the length
of hospital stay in stroke patients. Cerebrovasc Dis. 2003;16:247-252PubMed | Link to Article

References

Adams HP Jr, Adams RJ, Brott T.
et al. Guidelines for the early management of patients with ischemic stroke:
a scientific statement from the Stroke Council of the American Stroke Association. Stroke. 2003;34:1056-1083PubMed | Link to Article

Schmidt WP, Taeger D, Buecker-Nott HJ, Berger K. The impact of the day of the week and month of admission on the length
of hospital stay in stroke patients. Cerebrovasc Dis. 2003;16:247-252PubMed | Link to Article

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